Question regarding generics?

[Cloud 9]

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I'm trying to learn exactly what is the difference between generics and brand names.

This isn't homework help but it's a concept I'm slightly confused about and would like some more light on the topic and this is definitely something pharmacists would know more about.

So in my biochemistry class, the professor told us that generics are less expensive because they are cheaper to make since they usually have 50% of the L (or D form, whichever is inactive) and 50% of the active form.

So I'm wondering how is it that generics are as effective as brands if 50% is the inactive enantiomer? By that, shouldn't you need twice as much to make it as effective?

I asked a physician who told me that some of his patients swear that some generics are less effective. But he told me that at the same time, the generics have to be equal and so if he asks for 20 mg of a brand name he should be able to get 20 mg of a generic to be equal.

How is that so, if 50% of it is in inactive form?

 

[Praziquantel86]

I'm trying to learn exactly what is the difference between generics and brand names.

This isn't homework help but it's a concept I'm slightly confused about and would like some more light on the topic and this is definitely something pharmacists would know more about.

So in my biochemistry class, the professor told us that generics are less expensive because they are cheaper to make since they usually have 50% of the L (or D form, whichever is inactive) and 50% of the active form.

So I'm wondering how is it that generics are as effective as brands if 50% is the inactive enantiomer? By that, shouldn't you need twice as much to make it as effective?

I asked a physician who told me that some of his patients swear that some generics are less effective. But he told me that at the same time, the generics have to be equal and so if he asks for 20 mg of a brand name he should be able to get 20 mg of a generic to be equal.

How is that so, if 50% of it is in inactive form?

That's actually blatantly false, I really don't know what your professor was thinking.

A generic is the identical active ingredient, in the identical amount, with identical bioavailability. In other words, they are identical in all aspects aside from inactive binders, fillers and similar additives.

Many brand name drugs are marketed as a racemic mixture, and oftentimes only one of those enantiomers is active. If that's the case, then the generic is prepared the same way. If the brand is stereoselective, such as Keppra (leveteracetam), then the generic is also stereoselective. Not a hard concept.

 

[Cloud 9]

That's actually blatantly false, I really don't know what your professor was thinking.

A generic is the identical active ingredient, in the identical amount, with identical bioavailability. In other words, they are identical in all aspects aside from inactive binders, fillers and similar additives.

Many brand name drugs are marketed as a racemic mixture, and oftentimes only one of those enantiomers is active. If that's the case, then the generic is prepared the same way. If the brand is stereoselective, such as Keppra (leveteracetam), then the generic is also stereoselective. Not a hard concept.

Thanks for the information. Yeah it sounded so weird but it was actually a question on our quiz and the "answer" was similar to what he said that half is inactive which is why it's cheaper.

I thought his answer was wrong but whatever I guess.

When I get it back next week maybe I can post it to because he really did teach us that! >:(

So the real reason why it's cheaper is because the inactive fillers and additives are changed to something cheaper?

 

[bacillus1]

Thanks for the information. Yeah it sounded so weird but it was actually a question on our quiz and the "answer" was similar to what he said that half is inactive which is why it's cheaper.

I thought his answer was wrong but whatever I guess.

When I get it back next week maybe I can post it to because he really did teach us that! >:(

So the real reason why it's cheaper is because the inactive fillers and additives are changed to something cheaper?

It's cheaper because the generic manufacturer didn't have to spend the big bucks on the initial research to get the drug FDA approved, as well as the initial marketing for the drug. When patients ask, I usually focus on the research, not the marketing.

 

[TemSirolimus]

I'm trying to learn exactly what is the difference between generics and brand names.

This isn't homework help but it's a concept I'm slightly confused about and would like some more light on the topic and this is definitely something pharmacists would know more about.

So in my biochemistry class, the professor told us that generics are less expensive because they are cheaper to make since they usually have 50% of the L (or D form, whichever is inactive) and 50% of the active form.

So I'm wondering how is it that generics are as effective as brands if 50% is the inactive enantiomer? By that, shouldn't you need twice as much to make it as effective?

I asked a physician who told me that some of his patients swear that some generics are less effective. But he told me that at the same time, the generics have to be equal and so if he asks for 20 mg of a brand name he should be able to get 20 mg of a generic to be equal.

How is that so, if 50% of it is in inactive form?

your professor is fibbing.

 

[PumpkinSmasher]

So the real reason why it's cheaper is because the inactive fillers and additives are changed to something cheaper?

Don't confuse the raw costs of materials/manufacturing with the actual acquisition price.

 

[type b pharmD]

well

racemic mixtures are often cheaper because they are generics

single enantiomeric things are a relatively new concept, and as such, it just so happens that most of them are brand new, and thus, brand, and more expensive. single enantiomers are used as a form of evergreening in pharma industry

of course it's more expensive to manufacture enantioselectively (is that a word?) , but not ridiculously more expensive. wouldnt you just need a sieve

 

[Cloud 9]

Thank you guys, your explanations made a lot more sense.

So I think maybe he meant to word it this way?

That other than research & marking up the brand,

the pure drug -- if it begins in racemic form -- is more potent in its active enatiomer and due to evergreening it could be sold for more than the racemic mixture, after which, has become the generic?

 

[CUpharmD2013]

It's cheaper because the generic manufacturer didn't have to spend the big bucks on the initial research to get the drug FDA approved, as well as the initial marketing for the drug. When patients ask, I usually focus on the research, not the marketing.

This. Once the active ingredient is patented, the chemical structure is known to the world. It is up to generic manufacturers to come up with a manufacturing process for both the active ingredient and final dosage form. This is usually a simple process and doesn't require a lot of R&D expense. They then have to prove to the FDA that their product is bioequivalent to the brand name product. You'll learn about this at some point in your school career, but the FDA considers two products bioequivalent if the 90% CI of the relative mean Cmax, AUC(0-t) and AUC(0-&#8734😉 of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80.00% to 125.00% in the fasting state.

The reason that brand drugs are so expensive is three-fold:

1. Brand manufacturer is trying to recoup money spent to research, devleop, and market that particular drug.
2. They are also trying to recoup money spent to research and develop all those drugs that end up not making it to the market. Only about 5% of drugs that enter clinical trials actually make it to the market. This doesn't include all the drugs that fail prior to Phase I clinical trials.
3. They have to accomplish this in the amount of time that the brand is protected by the patent. Once the brand is no longer protected by the patent and goes generic, the brand company loses 90-95% of the marketshare. For instance, Lipitor sold $10.7 billion last year for Pfizer. Once it goes generic at the end of November of this year, they will be losing $9 billion or more in sales each year on this drug alone.

So basically, big Pharma companies do all the work and generic companies reap all the reward. Once a generic company has shown their process to meet the specifications above, they can get in line to market their product once the patent expires. To use Lipitor as an example again, Ranbaxy, an Indian manufacturer, will be the first to market generic Lipitor and will have market exclusivity for 180 days after patent expiration. Because that short window of exclusivity will be a gold mine for Ranbaxy, they have spent a lot of money on lawsuits to try to prove that the patent should expire sooner. You're also starting to see a lot of big Pharma companies buying or starting their own generic manufacturers so that they can continue to reap the benefits once the drug goes off patent.

 

[Cloud 9]

This. Once the active ingredient is patented, the chemical structure is known to the world. It is up to generic manufacturers to come up with a manufacturing process for both the active ingredient and final dosage form. This is usually a simple process and doesn't require a lot of R&D expense. They then have to prove to the FDA that their product is bioequivalent to the brand name product. You'll learn about this at some point in your school career, but the FDA considers two products bioequivalent if the 90% CI of the relative mean Cmax, AUC(0-t) and AUC(0-&#8734😉 of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80.00% to 125.00% in the fasting state.

The reason that brand drugs are so expensive is three-fold:

1. Brand manufacturer is trying to recoup money spent to research, devleop, and market that particular drug.
2. They are also trying to recoup money spent to research and develop all those drugs that end up not making it to the market. Only about 5% of drugs that enter clinical trials actually make it to the market. This doesn't include all the drugs that fail prior to Phase I clinical trials.
3. They have to accomplish this in the amount of time that the brand is protected by the patent. Once the brand is no longer protected by the patent and goes generic, the brand company loses 90-95% of the marketshare. For instance, Lipitor sold $10.7 billion last year for Pfizer. Once it goes generic at the end of November of this year, they will be losing $9 billion or more in sales each year on this drug alone.

So basically, big Pharma companies do all the work and generic companies reap all the reward. Once a generic company has shown their process to meet the specifications above, they can get in line to market their product once the patent expires. To use Lipitor as an example again, Ranbaxy, an Indian manufacturer, will be the first to market generic Lipitor and will have market exclusivity for 180 days after patent expiration. Because that short window of exclusivity will be a gold mine for Ranbaxy, they have spent a lot of money on lawsuits to try to prove that the patent should expire sooner. You're also starting to see a lot of big Pharma companies buying or starting their own generic manufacturers so that they can continue to reap the benefits once the drug goes off patent.

Wow, super explanation, thank you for expanding on that. So it really has nothing to do with the isomerism in most cases. Wow was I mislead ><
I really appreciate everyone taking the time to answer my juvenile questions, thank you, and I will note my prof is an idiot and move on 😛

 

[Naidim]

Wow, super explanation, thank you for expanding on that. So it really has nothing to do with the isomerism in most cases. Wow was I mislead ><
I really appreciate everyone taking the time to answer my juvenile questions, thank you, and I will note my prof is an idiot and move on 😛

The isomerism (racemic vs. "active" enantiomer) is how drug companies extend their patent in some cases.

e.g. Prilosec (omeprazole) was made and tested and marketed by AstraZeneca and made lots of money for many years. Then the patent expired and other companies can make generic versions of the same drug, lowering the cost and profit. So AstraZeneca makes (isolates), tests, and markets Nexium (esomeprazole) the S enantiomer only of the drug. Now they have the patent on the new drug for another 20 years.

It is of course different for every drug, however. Some enantiomers work better, worse, or not at all. Some drugs are racemized in vivo (thalidomide) so a single enantiomer has no benefit.

A few other racemic/enantiomer specific drugs:
modafinil - armodafinil
zopiclone - eszopiclone
citalopram - escitalopram

 

[xiphoid2010]

well

racemic mixtures are often cheaper because they are generics

single enantiomeric things are a relatively new concept, and as such, it just so happens that most of them are brand new, and thus, brand, and more expensive. single enantiomers are used as a form of evergreening in pharma industry

of course it's more expensive to manufacture enantioselectively (is that a word?) , but not ridiculously more expensive. wouldnt you just need a sieve

I was a medicinal chemist before pharm.D.

Racemic mixture is cheaper because making a single enantiomer basically falls into 2 methods:
(1) asymmetric synthesis: especially with a larger molecule or one with multiple chiral centers, are very difficult. Often requiring expensive chiral catalysts, and poor purity and yield.
(2) chiral separation: you cann't just do it in a sep-funnel or distillation. Separation often involve separation using custom resins that can be impossibly expensive to use on a large scale.

Not all drugs can be made or separated into a single enantiomer. And often it doesn't even matter. If the binding site has the same affinity for both enantiomer, who cares if it's -S vs. -R? It's more of an issue when the inactive enantiomer actually competitively inhibit the binding of the active one, or cause most of the side effects.

 

[Pharmavixen]

Recently, I got into an argument with the psychiatric nurse, who was insisting one of the inmates needed escitalopram specifically (I insist the drs substitute citalopram). The psychiatrist told her the inmate needed escitalopram "for its anti-OCD properties."

*headdesk*

 

[Pharmavixen]

Not all drugs can be made or separated into a single enantiomer. And often it doesn't even matter. If the binding site has the same affinity for both enantiomer, who cares if it's -S vs. -R? It's more of an issue when the inactive enantiomer actually competitively inhibit the binding of the active one, or cause most of the side effects.

Re the bolded part: are there drugs where that's therapeutically sig?

 

[rxlea]

Recently, I got into an argument with the psychiatric nurse, who was insisting one of the inmates needed escitalopram specifically (I insist the drs substitute citalopram). The psychiatrist told her the inmate needed escitalopram "for its anti-OCD properties."

*headdesk*

"There are studies reporting the efficacy of citalopram in OCD.9,10 The available data suggest that escitalopram possesses advantages over citalopram in terms of both efficacy and safety."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2139927/

EDIT: this is just one article with a few cases but I have seen others...

It could be legitimate.

 

[All4MyDaughter]

I'm not sure anyone will convince me that Lexapro has advantages over citalopram for anything, unless it can somehow be proven that the inactive isomer has some negative effect on efficacy or safety. After all, there is nothing IN Lexapro that isn't in citalopram.

Edit: I found two head to head studies, but they were small scale. From my quick read, it seems that the results were statistically significant, but perhaps not clinically significant, particularly if you consider economic factors. Is the added cost of Lexapro justified by greater efficacy in the majority of patients? I know my primary workplace has concluded (for now) that it is not. Citalopram is first line therapy. Lexapro is non-formulary.

Study 1: http://www.ncbi.nlm.nih.gov/pubmed/18158074

Study 2: http://www.ncbi.nlm.nih.gov/pubmed/15812262

Edit 2: I also think there is a certain amount of luck/guesswork involved when determining which SSRI patients respond to. It's highly patient specific.

 

[Praziquantel86]

Re the bolded part: are there drugs where that's therapeutically sig?

Theoretically levalbuterol/albuterol, but I don't really buy that one. Any of the dual-availability (both racemic and stereoselective) drugs on the market will have something in their literature about how the individual enantiomer is slightly better.

I think Keppra's dextro enantiomer is biologically inactive, but that's the only one I can think of off the top of my head that the stereoselectivity actually matters in vivo.

 

[All4MyDaughter]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2139927/

EDIT: this is just one article with a few cases but I have seen others...

It could be legitimate.

I'm not following how those case reports address the alleged superiority of Lexapro over citalopram. Those case reports detail patients who had success with Lexapro for OCD, but the patients were not necessarily non-responders to citalopram.

I used the references provided from your links to track down the two head to head studies I talked about above, but I don't think they are particularly impressive either.

 

[rxlea]

Like you said already, it is highly patient specific. If the patient in Vixen's post was already on Lexapro and it was working, I would be inclined to keep him on it. Messing with psych meds is a tricky business. But, I have seen other studies that pitted lexapro against celexa that were considered "clinically significant". I don't have time to dig them up right now. I would say that the literature isn't always convincing when dealing with isomers but, from what I have seen, and my own personal experience, it seems to matter more with certain medications. In this case, SSRIs. Feel free to prove me wrong. No doubt someone will disagree.

 

[All4MyDaughter]

Like you said already, it is highly patient specific. If the patient in Vixen's post was already on Lexapro and it was working, I would be inclined to keep him on it. Messing with psych meds is a tricky business. But, I have seen other studies that pitted lexapro against celexa that were considered "clinically significant". I don't have time to dig them up right now. I would say that the literature isn't always convincing when dealing with isomers but, from what I have seen, and my own personal experience, it seems to matter more with certain medications. In this case, SSRIs. Feel free to prove me wrong. No doubt someone will disagree.

I was just confused because you started out talking about how Lexapro might have better data vs citalopram, but referenced case reports that didn't address that issue at all.

I do agree that if a patient is tolerating and responding well to Lexapro and has no issues with the cost, there is no point in switching to another agent (citalopram or otherwise). But I also don't think that there is convincing evidence that we need to START with Lexapro in treatment naive patients.

Edit: Here's a link to an abstract purporting that the increased efficacy of Lexapro is due to an alleged inhibitory effect of the R isomer. But it's not conclusive either. http://www.ncbi.nlm.nih.gov/pubmed/15160261

 

[All4MyDaughter]

"There are studies reporting the efficacy of citalopram in OCD.9,10 The available data suggest that escitalopram possesses advantages over citalopram in terms of both efficacy and safety."

Also - the way this is quoted is somewhat misleading. And yes, I realize you were quoting this from somewhere else. The first sentence is true. Citalopram has been studied in OCD. But the second sentence suggests that there is data showing that Lexapro is safer and more effective than citalopram in OCD. I can't find ANY studies that suggest that. The only head to head studies that I am aware of (from my psych classes and rotation) looked at Lexapro vs citalopram in MDD, not OCD. Again, I'm referring to the two studies I linked to above. There may be others I'm not aware of.

 

[rxlea]

http://www.ncbi.nlm.nih.gov/pubmed/19367152
http://www.ncbi.nlm.nih.gov/pubmed/17675913
http://www.ncbi.nlm.nih.gov/pubmed/12876551
http://www.ncbi.nlm.nih.gov/pubmed/12842122

These are the few that popped up with a cursory search... I don't have time right now to go through each one since I am studying for an exam. Yes, these focus on depression but I don't see why that can't be applied to OCD as well considering the true issue is with the enantiomer having a counteracting effect... but, like always, it is patient specific and probably has something to do with genetics...

 

[xiphoid2010]

Re the bolded part: are there drugs where that's therapeutically sig?

That's a tough one, as you'll need to get the original binding data from the big pharma itself.

But I wouldn't say every single enantiomer drug is a marketing trick. I used to knock lexapro pretty hard, but it actually looks like it might be an example where the inactive isomer competes with the active one. I'm saying this based on the equivalency ratio of approximately 4:1 where 10 mg esitalopram approx equal to 40 mg citalopram. One explanation of it is that 1 isomer is inactive, but has the same binding affinity, so binds half of the time. removing allow the other to bind freely, quadrupling the effect. But that's just a guess.

 

[All4MyDaughter]

http://www.ncbi.nlm.nih.gov/pubmed/19367152
http://www.ncbi.nlm.nih.gov/pubmed/17675913
http://www.ncbi.nlm.nih.gov/pubmed/12876551
http://www.ncbi.nlm.nih.gov/pubmed/12842122

These are the few that popped up with a cursory search... I don't have time right now to go through each one since I am studying for an exam. Yes, these focus on depression but I don't see why that can't be applied to OCD as well considering the true issue is with the enantiomer having a counteracting effect... but, like always, it is patient specific and probably has something to do with genetics...

Right. Those are interesting articles that potentially address WHY there might be a difference between the two drugs, but they don't provide evidence that would substantially (IMO) influence clinical practice, at least not at this point.

What I think is missing is evidence from LARGE SCALE randomized, head to head clinical trials. The two I linked above were done in small study populations. And it's a difficult issue to study anyway because of the study population and the subjective nature of many psychiatric illnesses. There are numerous confounders.

I wish I had access to the VA clinical guidance documents on this issue. They are pretty comprehensive and well referenced. But I don't have remote access and won't be working for a while. Not sure I'd be permitted to post them outside the VA anyway. The geriatrics rotation I did there had a significant geropsych component and we looked into this extensively.

 

[All4MyDaughter]

That's a tough one, as you'll need to get the original binding data from the big pharma itself.

But I wouldn't say every single enantiomer drug is a marketing trick. I used to knock lexapro pretty hard, but it actually looks like it might be an example where the inactive isomer competes with the active one. I'm saying this based on the equivalency ratio of approximately 4:1 where 10 mg esitalopram approx equal to 40 mg citalopram. One explanation of it is that 1 isomer is inactive, but has the same binding affinity, so binds half of the time. removing allow the other to bind freely, quadrupling the effect. But that's just a guess.

I 😍 med chem! And psychiatry! This is definitely an issue that needs more study. I'm just not convinced yet about Lexapro.

And even if we prove that the difference exists, it still may not be clinically significant. Like the issue of Plavix and PPIs. There is an interaction, but there is new evidence that it may not be as clinically significant as thought previously. The VA is very interested in that evidence too, because they've been allowing people on Plavix to get Protonix instead of omeprazole. But Protonix costs a lot more and if it's unnecessary...

 

[rxlea]

I 😍 med chem! And psychiatry! This is definitely an issue that needs more study. I'm just not convinced yet about Lexapro.

And even if we prove that the difference exists, it still may not be clinically significant. Like the issue of Plavix and PPIs. There is an interaction, but there is new evidence that it may not be as clinically significant as thought previously. The VA is very interested in that evidence too, because they've been allowing people on Plavix to get Protonix instead of omeprazole. But Protonix costs a lot more and if it's unnecessary...

Can you expound on the MOA here? because I am really interested...

 

[All4MyDaughter]

Can you expound on the MOA here? because I am really interested...

The MOA of the interaction? PPIs can inhibit the metabolism of clopidogrel (via 2C19). Since clopidogrel is a prodrug, this could decrease its effectiveness in patients taking both agents.

Pharmacist's Letter has a really good analysis of the clinical significance of the interaction and discusses the available evidence on both sides of the issue. I reviewed the recently released COGENT trial that addressed the interaction of clopidogrel and omeprazle. Unfortunately, my copy of the PL article and my COGENT writeup are saved on my computer at the VA and I can't access them at the moment. 🙁

 

[CUpharmD2013]

The MOA of the interaction? PPIs can inhibit the metabolism of clopidogrel (via 2C19). Since clopidogrel is a prodrug, this could decrease its effectiveness in patients taking both agents.

Pharmacist's Letter has a really good analysis of the clinical significance of the interaction and discusses the available evidence on both sides of the issue. I reviewed the recently released COGENT trial that addressed the interaction of clopidogrel and omeprazle. Unfortunately, my copy of the PL article and my COGENT writeup are saved on my computer at the VA and I can't access them at the moment. 🙁

Yeah, we reviewed the COGENT trial recently too, but I don't have access to the writeup.

As for Lexapro vs. Celexa, we recently studied this in pharmacology and the previous poster was correct in saying that escitalopram is about 4x more selective for 5-HT receptors than citalopram with sertraline having about the same potency as escitalopram and paroxetine being about 7x more selective for 5-HT than escitalopram. The difference, though, is that paroxetine and sertraline have a much higher selectivity for NE receptors than escitalopram. Thus, if you use 5-HT/NE ratio as your measure of overall potency, escitalopram is 5x that of citalopram, 6x that of paroxetine, 8x that of sertraline, and 25x that of fluoxetine. I hope that all makes sense.

As of right now, Lexapro is supposed to go generic early next year. But that could change between now and then. I know that PL has a list (as of I think 6/2010) as to when medications are scheduled to go generic in the near future.

 

[Pharmavixen]

Like you said already, it is highly patient specific. If the patient in Vixen's post was already on Lexapro and it was working, I would be inclined to keep him on it.

I'm fairly proactive with the therapeutic substitution. In the case of citalopram vs escitalopram, they are basically the same drug. And in my experience generally, there isn't much difference between the SSRIs in terms of clinical efficacy, though I prefer citalopram because it doesn't mess with the CYP450 like some of the others (fluvoxamine, paroxetine, fluoxetine).

It's important to keep in mind when looking at clinical trials of antidepressants that most of them are funded by pharmaceutical manufacturers in the context of getting regulatory approval. In some cases, these trials were short in duration and had strict exclusion/inclusion criteria that are not so representative of the messy world of actual clinical practice. You may see, for instance, statistically significant improvements in HAM-D scores, but the clinical significance of these is not so clear.

The Ciprani 2009 systematic review/MA is used to justify the superiority of escitalopram. All the odds ratios (except one) were < 2, the quality of the included trials were unclear, placebo-controlled trials were excluded (and the placebo effect in psychiatry can be huge), and only 14 studies out of 117 had a follow-up of longer than 12 weeks.

It's also problematic to compare older trials and older agents with newer trials and agents because trial methodologies have evolved over the years. So the supposed superiority of escitalopram may be an artifact of the methodology of clinical trials, since it's a newer agent than the others.

My bottom line: I continue to substitute citalopram for escitalopram with impunity. Statistical significance &#8800; clinical significance.

 

[Pharmavixen]

As for Lexapro vs. Celexa, we recently studied this in pharmacology and the previous poster was correct in saying that escitalopram is about 4x more selective for 5-HT receptors than citalopram with sertraline having about the same potency as escitalopram and paroxetine being about 7x more selective for 5-HT than escitalopram. The difference, though, is that paroxetine and sertraline have a much higher selectivity for NE receptors than escitalopram. Thus, if you use 5-HT/NE ratio as your measure of overall potency, escitalopram is 5x that of citalopram, 6x that of paroxetine, 8x that of sertraline, and 25x that of fluoxetine. I hope that all makes sense.

I also 😍 medchem, but the pathophysiology of depression remains an enigma. All these differing receptor affinities impact on dosing, but otherwise we don't see differences in the SSRIs clinically.

 

[rxlea]

I'm sorry Vixen but with most other drugs I would agree with you. Just not psych meds. I will post more later (I have to go to class) but messing with someone's psychmeds (including switching to generic with drugs like lamotrigine) is risky. Would you adjust a bipolar patient's meds because a certain D2 antagonist is not on formulary?

 

[Pharmavixen]

I'm sorry Vixen but with most other drugs I would agree with you. Just not psych meds. I will post more later (I have to go to class) but messing with someone's psychmeds (including switching to generic with drugs like lamotrigine) is risky.

Depends on the psych med and the specific psychiatric pathophysiology. A typical situation I'd see is a guy with badly-controlled depression complicated by substance abuse, no hx of psychosis, and taking escitalopram started by a PCP, that the pt may or may not have been compliant with at all. If a pt is compliant, and has had a successful mitigation of his depression, I'd consider keeping the meds the same. But I never see that.

Would you adjust a bipolar patient's meds because a certain D2 antagonist is not on formulary?

Nope, for a few reasons. Firstly, we carry all the D2 antagonists. And in my experience, I have seen severely psychotic pts stabilized on one D2, and then switched to another by a penny-pinching physician at another jail who was appalled at the price of Zyprexa, and then the guy is transferred back to us relapsed into a severely psychotic state. I don't see this happen with the SSRIs, who have not been found to have vastly clinically different efficacies.

And a lot of the folks given SSRIs seem to be, in the opinion of our psychiatrists, a mix of Axis II (personality disorders) and Axis I. Personality disorders are extremely refractory to treatment. A typical picture: guy comes in on escitalopram 20 mg qam, bupropion XL 300 mg once daily, and quetiapine or trazodone 50 mg hs for sleep. And this person is still dysfunctional as hell.

The pts with definite Axis I disorders, say bipolar type I and schizophrenia, that relapse into pychosis/mania are qualitatively different than non-psychotic pts on SSRIs, who seem to be equally bummed out whether they are on their SSRI or not. I'm not all that impressed with the efficacy of SSRIs in general - like I mentioned in my previous post, the placebo effect is huge, and a statistically significant reduction in HAM-D scores in a clinical trial doesn't necessarily mean that pts are clinically better in a real sense. When it comes to depression, the evidence, the tx, and the determination of efficacy are largely based on subjective measures.

 

[All4MyDaughter]

vixen, great posts. All of them. I agree with pretty much every word. Especially with this point, particularly as it pertains to SSRIs (but other drugs as well):

My bottom line: I continue to substitute citalopram for escitalopram with impunity. Statistical significance &#8800; clinical significance.

If there is one thing I've learned this year through my 1001 journal club presentations it is that you can find a statistically significant difference between many things, but whether that difference is important to patient care and substantial enough to affect clinical practice is a completely different matter.

There's no comparison between switching SSRIs and switching D2 antagonists. For the reasons you mentioned PLUS the D2 antagonists have significantly different side effect profiles. There is plenty of evidence out there to support the known differences in D2 antagonists, but that evidence just isn't there for SSRIs. Plus, every place I've worked has had ALL (or almost all) the D2 antagonists on formulary (although I'm not 100% sure that the VA carries Invega) so switching for formulary reasons doesn't really happen much anyway.

 

[rxlea]

Thanks for the info!

 

[All4MyDaughter]

Yeah, we reviewed the COGENT trial recently too, but I don't have access to the writeup.

As for Lexapro vs. Celexa, we recently studied this in pharmacology and the previous poster was correct in saying that escitalopram is about 4x more selective for 5-HT receptors than citalopram with sertraline having about the same potency as escitalopram and paroxetine being about 7x more selective for 5-HT than escitalopram. The difference, though, is that paroxetine and sertraline have a much higher selectivity for NE receptors than escitalopram. Thus, if you use 5-HT/NE ratio as your measure of overall potency, escitalopram is 5x that of citalopram, 6x that of paroxetine, 8x that of sertraline, and 25x that of fluoxetine. I hope that all makes sense.

As of right now, Lexapro is supposed to go generic early next year. But that could change between now and then. I know that PL has a list (as of I think 6/2010) as to when medications are scheduled to go generic in the near future.

Once Lexapro goes generic, it won't really matter because it will finally be affordable to patients and just another SSRI to try when patients don't respond to one or another. My problem with it right now is that the pharmaceutical industry has done a bang up job of convincing the public, physicians and even pharmacists that Lexapro is SO much more effective than citalopram (or other cheaper agents) and PCPs start everyone on it. It's too expensive and the evidence that it is "the best" simply isn't there. I also don't like Pristiq. 👎

COGENT... let's see what I can remember. It was to test a novel dosage form that had clopidogrel AND omeprazole in the same capsule with a delayed release mechanism for one of them (so they weren't released together). An interim analysis found no increased risk from using the two agents together (in conflict with earlier results) but the trial ended early b/c the sponsor went bankrupt. I remember having some issues with the study design or the inclusion criteria or something... can't recall specifics. I do know that my conclusion was something along the lines of "Interesting But Needs More Study..." 🙂

Speaking of clinical vs. statistical significance - I reviewed an article about apixiban for A fib that showed that apixiban was better than aspirin for patients who have A fib and are at increased risk for stroke. Statistically significant results and all. But the average CHADS2 score for patients in the study was 2, so aspirin isn't an appropriate choice for most of those patients anyway. The treatment of choice is warfarin. But for whatever reason, the manufacturers of apixiban haven't done a head to head with warfarin... wonder why??? That's a good example of a study where the results were "significant" but won't be affecting clinical practice anytime soon.

 

[xiphoid2010]

Speaking of clinical vs. statistical significance - I reviewed an article about apixiban for A fib that showed that apixiban was better than aspirin for patients who have A fib and are at increased risk for stroke. Statistically significant results and all. But the average CHADS2 score for patients in the study was 2, so aspirin isn't an appropriate choice for most of those patients anyway. The treatment of choice is warfarin. But for whatever reason, the manufacturers of apixiban haven't done a head to head with warfarin... wonder why??? That's a good example of a study where the results were "significant" but won't be affecting clinical practice anytime soon.

Are you talking about AVERROES trial? If so, they were comparing apixaban to ASA for patients who can't take warfarin. So it's not they didn't compared the right drugs, but it was an issue of a niche study. My first response was "no-duh", we already know that ASA isn't enough for stroke prevention for a CHAD score 2 or more.

Another rather inconclusive/no-duh trial. COGENT trial. We already know that PPIs reduce GI bleed. Once you take that part of the results out, you realized it didn't answer whether there was a significant interaction between PPI and plavix at all. And the fact it couldn't finish and was under powered made it all but useless in light of the negative finding.

 

[All4MyDaughter]

Are you talking about AVERROES trial? If so, they were comparing apixaban to ASA for patients who can't take warfarin. So it's not they didn't compared the right drugs, but it was an issue of a niche study. My first response was "no-duh", we already know that ASA isn't enough for stroke prevention for a CHAD score 2 or more.

Another rather inconclusive/no-duh trial. COGENT trial. We already know that PPIs reduce GI bleed. Once you take that part of the results out, you realized it didn't answer whether there was a significant interaction between PPI and plavix at all. And the fact it couldn't finish and was under powered made it all but useless in light of the negative finding.

Yeah, both pretty ho hum in terms of results. But they were statistically significant!!! 😛

And yeah, AVERROES was a niche study. But I think they went after the "can't/don't wanna/shouldn't/skeered" to take warfarin niche vs. ASA first b/c they didn't want to go head to head with warfarin. Clearly, warfarin would be the bigger target. No one wants to bring an expensive drug to market for a niche population. And I think apixiban will make it to market (if it gets approved) too late. There are other options already out that seem more promising.

People at work were pretty excited about COGENT. But I don't think it settles anything.